tbuckley/cabot-search huggingface dataset:
Research ethics systems in Latin America and the Caribbean: a systemic assessment using indicators
Authors: Bernardo Aguilera, Sarah Carracedo, Carla Saenz
Journal: The Lancet Global Health (2022)

To strengthen research ethics systemically, the Pan American Health Organization (PAHO) devised a strategy that includes objectives and indicators to address core components of research ethics systems. We assessed 22 countries in Latin America and the Caribbean using these indicators. Most countries have adopted legal instruments to govern research with human participants and have implemented national bodies tasked with the oversight of research ethics committees. However, performance with regard to ethics training policies and clinical trial registration was less advanced, and efforts to adopt policies on responsible conduct of research and accelerated ethics review of emergency research did not meet the PAHO objectives in most countries. We discuss the pending challenges and provide recommendations aimed at helping countries from Latin America and the Caribbean to achieve the indicators, and, more generally, to strengthen research ethics with a systemic approach.
Abstract 974: Genome-wide analysis of estrogen receptor b binding sites: Implications for endogenous anti-metastatic activity in inflammatory breast cancer
Authors: Ilias V. Karagounis, Spyros Tastsoglou, Anna Karavangeli, Amit Maity, Artemis Chatzigeorgiou, Christoforos Thomas
Journal: Cancer Research (2022)

Abstract Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor a (ERa) negativity. We previously explored the second ER subtype, (ERb) and reported expression in IBC tumors and its correlation with reduced metastasis in patients. We have also seen decreased metastasis of IBC tumors when ERb is expressed or activated by chemical agonists. In contrast, ablation of ERb in IBC cells increased migration and stimulated signaling pathways that activate Rho GTPases promoting actin reorganization. We have now mapped all ERb binding sites in IBC cells and by interrogating this information together with gene expression data we identified genomic targets that mediate its tumor repressive effects. Through a combined analysis of cells that express endogenous ERb and knockout cells engineered to re-express the receptor we have defined how a biologically relevant ERb interacts with the cancer cell genome to control metastatic signals in IBC. We reveal key binding motifs and cis-regulatory chromatin sites and associate target genes with clinical outcomes to strengthen the relevance of ERb signaling for the progression of IBC. Our findings thus offer an opportunity to better understand the mechanism of ERb action that is critical step in validating its tumor repressive role in breast cancer. Citation Format: Ilias V. Karagounis, Spyros Tastsoglou, Anna Karavangeli, Amit Maity, Artemis Chatzigeorgiou, Christoforos Thomas. Genome-wide analysis of estrogen receptor b binding sites: Implications for endogenous anti-metastatic activity in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 974.
Abstract 5949: Aspirins metabolites inhibit human colon cancer cell growth: Potential role in colorectal cancer prevention
Authors: Poojitha Tummala, Ranjini Sankaranarayanan, Rakesh Dachineni, Jayarama Gunaje Bhat
Journal: Cancer Research (2022)

Abstract Aspirin’s role in colorectal cancer (CRC) prevention is evidential from several epidemiological data. Numerous theories and targets have been proposed, a consensus has not been reached regarding its mechanism of action. One of the unexplored area in aspirin’s CRC prevention is the role of Dihydroxy benzoic acids (DHBAs), which are generated from aspirin’s metabolism by gut microflora and cytochrome P450 (CYP450). Out of the screened DHBAs, 2,3-DHBA and 2,5-DHBA showed concentration dependent inhibition of CDK1, CDK2, CDK4 and CDK6 enzyme activity in-vitro. We demonstrated that 2,3-DHBA and 2,5-DHBA inhibits CDK-1 enzyme activity beginning at 500 µM, while CDK2 and CDK4 activity was inhibited only at higher concentrations (&amp;gt;750 µM). 2,3-DHBA inhibited CDK6 enzyme activity from 250 µM, while 2,5-DHBA inhibited its activity &amp;gt;750 µM. Using colony formation assays, we further demonstrated the role of 2,3-DHBA and 2,5-DHBA in cancer cell cycle inhibition in 3 different cancer cell lines. Out of the 2 DHBAs, 2,5-DHBA was highly effective in inhibiting clonal formation in HCT-116 and HT-29 CRC cell lines (250-500 µM), and in the MDA-MB-231 breast cancer cell line (~100 µM); whereas both aspirin and salicylic acid failed to inhibit all four CDKs and colony formation. Based on the present results, it is suggested that 2,3-DHBA and 2,5-DHBA may contribute to the chemopreventive properties of aspirin, possibly through the inhibition of CDKs. The present data and the proposed mechanisms should open new areas for future investigations. Citation Format: Poojitha Tummala, Ranjini Sankaranarayanan, Rakesh Dachineni, Jayarama Gunaje Bhat. Aspirins metabolites inhibit human colon cancer cell growth: Potential role in colorectal cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5949.
Abstract 1527: Developing a multifaceted approach to target androgen receptor (AR) in castration resistant prostate cancer
Authors: Uttara Saran, Balaji Chandrasekaran, Ashish Tyagi, Subhasish Tapadar, Bocheng Wu, Oyelere Adegboyega, Chendil Damodaran
Journal: Cancer Research (2022)

Abstract Androgen receptor (AR) signaling is also regulated epigenetically by histone-modifying enzymes (histone deacetylases-HDACs) that result in the development and progression of prostate cancer (CaP). It has been established that the inhibition of HDACs suppresses CaP proliferation by inhibiting AR signaling via multiple mechanisms, including AR degradation. Hence, the goal of this study was to develop small molecules that employ multiple mechanisms to inhibit AR expression and promote its degradation, which would effectively control the emergence and treatment of castration-resistant prostate cancer (CRPC). Several rationally designed antiandrogen equipped HDAC inhibitors (HDACis) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo models. Results demonstrated that these compounds' target (HDAC and AR) binding properties translated into potent anticancer activity against AR+ CRPC cell lines and to a lesser extent in AR- CRPC cell lines. In addition, among these compounds, we found that SB-146, a nontoxic agent, not only inhibited the growth of AR+ CRPC cells at nanomolar IC50s without sparing toxicity to healthy prostate epithelial cells. Molecular analysis confirmed SB-146 downregulated the expressions of both AR and AR-spice variants (AR-SV) in CRPC cells. Further analyses revealed downregulation of AR downstream (PSA, HOXB13 and FOXA1) targets as well as AR-SV’s (NUP210 and SLC3A2) in CRPC cells. SB-146 was also able to overcome DHT-induced AR and AR-SV signaling in C4-2B and 22Rv1 cells. Assessment of SB-146’s therapeutic efficacy on in vivo models revealed that oral administration of this compound abrogated AR+ and AR-SV (C4-2B and 22Rv1) tumor growth in xenotransplanted nude mice models. Finally, immunohistochemical analysis confirmed SB-146’s target of both AR and AR-SVs on xenografted tumor tissues. Together these results confirm that SB-146 is a potent agent that inhibits AR signaling in CRPC cells. Citation Format: Uttara Saran, Balaji Chandrasekaran, Ashish Tyagi, Subhasish Tapadar, Bocheng Wu, Oyelere Adegboyega, Chendil Damodaran. Developing a multifaceted approach to target androgen receptor (AR) in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1527.
Abstract 3776: Frequent alteration of mitochondria functional pathways in lung cancer
Authors: Kate L. Hertweck, Brian Persing, Pranitha Prodduturvar, Seema Singh, Ajay Singh, Santanu Dasgupta
Journal: Cancer Research (2022)

Abstract Lung cancer killed 1.8 million people globally in 2020. In the United States, there will be over 235,760 cases of lung cancer with an estimated death of 131,880 individuals in 2021. Despite significant improvement in multimodal therapeutic approaches, overall 5-year survival rate is only 21.7%. Lung cancer appears to be mitochondria enriched cancer, however, alteration pattern of hallmark molecular pathways associated with diverse mitochondrial functions remain largely unknown in lung tumorigenesis. Utilizing high-throughput genomic profiling, we identified altered copy number of a panel of 40 mitochondria targeted molecules in primary lung cancer patients and their histologically normal appearing follow up mucosal biopsies. These altered molecules are critical components of the mitochondrial protein carrier, OXPHOS, stress response, amino acid metabolism and apoptosis pathways. This finding suggests for clonal genetic relationship between multifocal lesions and potential role of these alterations in the evolution of second primary tumors, which is an existing problem among lung cancer patients. The Human Cancer Genome Atlas database was utilized to further assess the mRNA expression pattern of these 40 molecules and determine their clinico-pathological correlations. Immunohistochemistry and digital pathology system based evaluations were performed to validate expression pattern of key altered molecules. We identified overexpression of various critical mitochondria pathway molecules including AARS2, AGMAT, SDHA, NDUFB7, LONP1, DGUOK, MRM1 and GCAT in both lung adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC), predicting poor prognosis. Significant loss of expression of ACSF2, ACSS1, MTCH1, SLC25A4, ACAD8 and NAGS was evident in both adenocarcinoma and squamous cell carcinoma subtypes. Molecular characterization of both LUAD and LUSC tumor subtypes identified significant association of various key molecules including ACAD8, AGMAT, DGUOK and NDUFAB1 with proximal-inflammatory, proximal-proliferative and terminal respiratory unit pathways in LUAD; and an association of DGUOK, MDH2, MRM1 and MRPL10 with basal, classical, primitive and secretory pathways in LUSC. Significant loss of SLC25A4 protein expression was evident in lung cancer tissues, which predicted poor survival of the lung cancer patients. Capturing the compendium of hallmark mitochondrial alterations in lung tumorigenesis may open up novel avenues for therapeutic and biomarker interventions to improve the overall survival of the lung cancer patients. Citation Format: Kate L. Hertweck, Brian Persing, Pranitha Prodduturvar, Seema Singh, Ajay Singh, Santanu Dasgupta. Frequent alteration of mitochondria functional pathways in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3776.
Abstract 3291: Anti-HER2 scFv antibody-directed lentiviral delivery of myrosinase for eradicating HER2+ cancer cells after dosing prodrug sinigrin
Authors: Ammar Ahmad Tarar, Ching-An Peng
Journal: Cancer Research (2022)

Abstract Chemotherapy is widely used for the treatment of cancers, but it lacks selectivity and therefore results in collateral damage to healthy cells and drug resistance of cancer cells. Gene-directed enzyme prodrug therapy (GDEPT) has been adopted to mitigate these issues. In this study, we demonstrated the specific targeting of myrosinase-sinigrin paired GDEPT to treat HER2+ (human epidermal growth factor 2) cancer cells. Sinigrin excessively present in cruciferous vegetables can be catalyzed by myrosinase to produce cytotoxic ally isothiocyanate (AITC), which has shown anticancer effectiveness. The myrosinase gene was packed in biotinylated lentiviral vectors produced by co-transfection of HEK293T cells. The single chain variable fragment (scFv) gene sequence of anti-HER2 antibody and core streptavidin (coreSA) gene sequence were cloned in pET-30a(+) plasmid, which was then transformed in Lemo21 (DE3) competent cells for protein expression. The anti-HER2-coreSA chimeric protein was purified using immobilized metal affinity chromatography and characterized by SDS-PAGE and Western blot. The purified chimeric protein was tagged on biotinylated lentivirus via streptavidin-biotin binding. Our results showed that myrosinase-encoding lentivirus tagged with anti-HER2 selectively delivered myrosinase to HER2+ cancer cells. When treated with prodrug sinigrin, the targeted cancer cells underwent apoptosis and ensuing cell death. In summary, the targeted delivery of myrosinase to HER2+ cancer cells using lentivirus functionalized with anti-HER2 ScFv antibody can eradicate malignant cells when treated with enzymatically catalyzed prodrug sinigrin. Citation Format: Ammar Ahmad Tarar, Ching-An Peng. Anti-HER2 scFv antibody-directed lentiviral delivery of myrosinase for eradicating HER2+ cancer cells after dosing prodrug sinigrin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3291.
Abstract 5824: Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism
Authors: Mei-Juan Tu, Frank J. Gonzalez, Ai-Ming Yu
Journal: Cancer Research (2022)

Abstract Tumor progression is accompanied by metabolic reprogramming to allow carcinoma cells to access essential nutrients under the tumor microenvironment. To meet energetic and material needs for high-rate proliferation and tumorigenesis, cancer cells generally rely more heavily on vital nutrients (e.g., glucose, amino acids, and vitamins) than normal cells. Therefore, controlling nutrient transport and metabolism in cancer cells is a promising therapeutic strategy. Our previous studies have suggested that microRNA-1291-5p (miR-1291-5p or miR-1291) is downregulated in pancreatic cancer (PC) cells and acts as a tumor suppressor. The current study is to delineate the role of miR-1291 in the control of PC cell metabolism and develop miR-1291 therapy. We first employed our newly-invented RNA bioengineering technology to achieve high-level and large-scale, in vivo fermentation production of a fully-humanized biologic miR-1291 agent at a high degree of homogeneity (&amp;gt; 4 mg BioRNA per liter of culture and &amp;gt; 97% purity). RNA sequencing studies revealed that BioRNA/miR-1291 was selectively processed to target miR-1291-5p to modulate the transcriptome in PC cells. Proteomics study showed that a number of proteins were reduced remarkably in AsPC-1 cells by biologic miR-1291-5p, among which PNPO, an enzyme that mediates the synthesis of essential nutrient vitamin B6 (VB6), was revealed as a leading target of miR-1291-5p. Besides PNPO and the previously-reported glucose transporter SLC2A1/GLUT1, amino acid transporter SLC7A5/LAT1 was verified as a direct target for miR-1291-5p. Downregulation of PNPO, LAT1, GLUT1 protein expression by biological miR-1291 led to sharp alteration of homeostasis of glucose, amino acids, and VB6 in human PC cells, and subsequent suppression of glycolysis capacity and mitochondrial function as well as the increase of oxidative stress. Combination treatment with bioengineered miR-1291 and 5-FU exerted strong synergism in the inhibition of PC cell and organoid proliferation in vitro. In addition, miR-1291 mono- and combination therapy were effective to control tumor growth in pancreatic cancer patient-derived xenograft (PDX) mouse models. These results demonstrate a critical role for miR-1291 in the regulation of PC cell metabolism which provides insight in developing new therapeutic strategies for PC. Citation Format: Mei-Juan Tu, Frank J. Gonzalez, Ai-Ming Yu. Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5824.
Abstract 1824: EZH2 inhibition induces blast differentiation in acute myeloid leukemia
Authors: Sydney Fobare, Ola A. Elgamal, Emily H. Stahl, Abeera Mehmood, Jean Truxall, Mariah L. Johnson, Amina Abdul-Aziz, John C. Byrd, Erin Hertlein
Journal: Cancer Research (2022)

Abstract Enhancer of zeste homolog 2 (EZH2) is a part of the polycomb repressive complex and catalyzes the trimethylation of lysine 27 on histone H3 (H3K27me3). EZH2 inhibition has a complex role in the pathogenesis of acute myeloid leukemia (AML), in that it has been shown to be either a tumor suppressor or an oncogene depending on the stage of AML development and the genes that EZH2 is regulating during each stage. Unlike follicular and diffuse large B-cell lymphoma where EZH2 mutations result in gain of function, EZH2 mutations are typically loss of function in myeloid diseases. However, we hypothesized that in AML patients without EZH2 mutations, loss of EZH2 function may produce a phenotype that would allow for therapeutic targeting without influencing normal hematopoiesis. We used EPZ011989 (EPZ), an EZH2 inhibitor tool compound, to inhibit H3K27me3 in our studies. We started by treating the MOLM-13 AML cell line with EPZ and confirmed a decrease in H3K27me3. This reduction in H3K27me3 resulted in a slight decrease in metabolic activity via MTS assays as well as decreased colony formation in methocult. These studies were followed up with EPZ inhibition in primary AML samples in vitro. We found that EZH2 inhibition resulted in decreased self-renewal of primary AML samples but not of CD34+ bone marrow cells from normal donors. Furthermore, we found that after 7-day treatment with EPZ, primary AML samples undergo moderate differentiation as suggested by an increase in CD11b surface expression via flow cytometry. These results are further supported by the morphological changes seen after 14-days of EPZ treatment in vitro. Based on these results, we hypothesize that EZH2 inhibition in primary AML samples promotes the differentiation of AML blasts. Furthermore, our preliminary data suggests that daily treatment with 150 mg/kg of EPZ results in a survival advantage and reduced disease burden in the MOLM-13-luciferase murine xenograft model. Despite loss of function EZH2 mutations portending poor outcomes in myeloid malignancies, we demonstrate that pharmacologic EZH2 inhibition reduces AML blast stemness and promotes differentiation into mature myeloid cells. In contrast, no change in normal CD34+ stem cells occurs with EZH2 inhibition, offering the opportunity to selectively target myeloid leukemia. Citation Format: Sydney Fobare, Ola A. Elgamal, Emily H. Stahl, Abeera Mehmood, Jean Truxall, Mariah L. Johnson, Amina Abdul-Aziz, John C. Byrd, Erin Hertlein. EZH2 inhibition induces blast differentiation in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1824.
Abstract 6270: Integrating spatial transcriptomics and single-cell RNA-seq reveal the tumorigenesis and heterogeneity of esophageal squamous cell carcinoma
Authors: Xiaoyang Yin, Baosheng Li
Journal: Cancer Research (2022)

Abstract Background: Esophageal cancer is the sixth leading cause of cancer death globally and esophageal squamous cell carcinoma (ESCC) is the major histological type in China. The heterogeneity of ESCC resulted in poor therapeutic effect and tumor recurrence. To investigate the heterogeneity of ESCC at the single-cell level and the oncogenic evolution, we performed single-cell RNA-seq and spatial transcrtiptomics analysis in ESCC samples from different patients and position. Methods: We performed single-cell RNA-seq of tumor, adjacent normal tissue and the junction of cancer and normal tissues from 4 ESCC patients. We also performed spatial transcriptomics of paired cancer, normal and junction of ESCC patients. Unsupervised clustering was performed to find different cell clusters of ESCC and marker genes of different clusters were determined. Inferred copy number variation was performed to identify malignant cells and pseudotime analysis to investigate the development of different cell clusters. Combined analysis of single-cell and spatial data was performed to reveal the spatial characteristics of different cell types. Results: We successfully determined different cell types including epithelial cells, immune cells, fibroblasts, myeloid cells and so on. And we also reclustered epithelial, myeloid and T/NK cells to investigate different subtypes and their marker genes. We also distinguished malignant cells from heterogeneous cellular populations using inferred copy number variation analysis. Pseudotime analysis revealed the evolution of different cell types of ESCC. We identified key signatures associated with oncogenic evolution of ESCC and the spatial characteristics of key cell clusters. Conclusion: These findings reveal the heterogenesis of ESCC and key signatures in ESCC tumorigenesis. Keywords: ESCC, single cell sequencing, spatial transcriptomics, heterogeneity, tumorigenesis Citation Format: Xiaoyang Yin, Baosheng Li. Integrating spatial transcriptomics and single-cell RNA-seq reveal the tumorigenesis and heterogeneity of esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6270.
Abstract 3536: Modulating T cell tumor infiltration by modulating T cell migration
Authors: Adrian Johnston, Frisco Du, Zeqi Wan, Cameron Lee, Yeongseo Lim, Michelle Bessiake, Praful Nair, Pei-Hsun Wu, Denis Wirtz
Journal: Cancer Research (2022)

Abstract Traditional assessments of T cells killing cancer cells are routinely done in two-dimensional cell culture wells and plates. The general methods comprise developing a cancer cell monolayer then overlaying it with T cells, or, worse, pre-mixing cancer cells with T cells before placing the mixture into culture wells/dishes. Such methods obviously force cancer cell-T cell interactions. This is not physiological, since T cells must migrate to tumors for cancer cell killing to even occur. Migration is a little-explored, yet central parameter ignored in 2D killing assays. There is no tumor cell killing by T cells if there is no T cell migration, biased or unbiased. Our work making use of novel 3D multi-compartments organoids systems identifies key molecules regulating pathways for T cell migration in 3D. We are currently testing molecules currently FDA-approved or in clinical trials that block or enhance T cell killing of cancer cells by blocking or enhancing T cell migration through a first-of-its-kind 3D killing assay that we developed. Citation Format: Adrian Johnston, Frisco Du, Zeqi Wan, Cameron Lee, Yeongseo Lim, Michelle Bessiake, Praful Nair, Pei-Hsun Wu, Denis Wirtz. Modulating T cell tumor infiltration by modulating T cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3536.